Adaptation of the heart to chronic pressure overload leads to cardiac hypertrophy and alterations in signal transduction to compensate for increased sympathetic tone and work. These adaptive changes lead to increases in cGMP levels down regulation of beta adrenergic receptors. The hypothesis of this proposal is that the negative functional effects of cGMP contribute to compensation in hypertrophy and that, when this endogenous brake fails, heart failure develops. The specific aim is to determine if the mechanism of cGMP's negative impact is through changes in cAMP via the cGMP-dependent cAMP phosphodiesterases (PDE) or through interactions of protein kinase G on A and C, to elucidate which of these mechanisms causes the hypertrophied heart to decompensate by contrasting the alterations in the signaling cascade of the compensated with that of failing hypertrophied heart (rapid pacing) and to confirm their relevance by further chronic alteration of the cAMP PDEs. Cardiac myocytes isolated from adult dogs with normal, hypertrophied (aortic stenosis model) and failing hearts will be used to determine the effects of postproduction changes in signaling on function (video edge detection) and O2 consumption (PO2 electrode). The relative importance of these mechanisms in controlling regional function and O2 costs will be tested in the intact heart. The in vivo experiments will be conducted in anesthetized, open-chest dogs 6 months after induction of hypertrophy with or without failure and compared to controls. Regional myocardial work will be assessed from segment length (ultrasonic dimension crystals) and contractile force (miniature force gauges). O2 consumption of the same area will be determined from regional blood flow (radioactive microspheres or flow probe) and regional O2 saturation of hemoglobin (microspectrophotometry). These physiological measurements will be combined with biochemical assays for cAMP, cGMP, the respective phosphodiesterases and protein kinases A, G and C and correlated with Ca transient measurements. The ultimate goal is to determine the mechanism that initiates decompensation and leads to congestive heart failure. Impact of the proposal: the understanding of these mechanisms will permit the development of new therapeutic strategies to prevent the development of congestive heart failure in man.